CN105622444B - The preparation method of 1- benzyl -3- piperidone hydrochlorides - Google Patents
The preparation method of 1- benzyl -3- piperidone hydrochlorides Download PDFInfo
- Publication number
- CN105622444B CN105622444B CN201511027904.4A CN201511027904A CN105622444B CN 105622444 B CN105622444 B CN 105622444B CN 201511027904 A CN201511027904 A CN 201511027904A CN 105622444 B CN105622444 B CN 105622444B
- Authority
- CN
- China
- Prior art keywords
- alkali
- ethyl
- preparation
- reaction
- halogenated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- OVWSFXNSJDMRPV-UHFFFAOYSA-N 1-benzylpiperidin-3-one;hydron;chloride Chemical class Cl.C1C(=O)CCCN1CC1=CC=CC=C1 OVWSFXNSJDMRPV-UHFFFAOYSA-N 0.000 title description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 22
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 20
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical class CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000012141 concentrate Substances 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical class OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical class CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 2
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical class CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 208000006278 hypochromic anemia Diseases 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims 2
- 239000000284 extract Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- KDHKOJFFKXGPKZ-UHFFFAOYSA-N piperidin-3-one;hydrochloride Chemical compound Cl.O=C1CCCNC1 KDHKOJFFKXGPKZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000002390 rotary evaporation Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 238000001514 detection method Methods 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- BBQQULRBTOMLTC-UHFFFAOYSA-N 1-benzylpiperidin-3-one Chemical class C1C(=O)CCCN1CC1=CC=CC=C1 BBQQULRBTOMLTC-UHFFFAOYSA-N 0.000 description 5
- 239000004519 grease Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- GKECDORWWXXNRY-UHFFFAOYSA-N 2h-pyridin-3-one Chemical class O=C1CN=CC=C1 GKECDORWWXXNRY-UHFFFAOYSA-N 0.000 description 4
- SJUWEPZBTXEUMU-LDXVYITESA-N 7-bromo-6-chloro-3-[3-[(2s,3r)-3-hydroxypiperidin-2-yl]-2-oxopropyl]quinazolin-4-one;hydrobromide Chemical compound Br.O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 SJUWEPZBTXEUMU-LDXVYITESA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- -1 halogen quinoline ketone Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 230000000410 anti-febrile effect Effects 0.000 description 2
- 229950000805 balofloxacin Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- VWUGNBHOYLFPRZ-UHFFFAOYSA-N dichroanone Natural products CC(C)C1=C(O)C(=O)C2=C(C=C3C(C)(C)CCCC23C)C1=O VWUGNBHOYLFPRZ-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- UEHVFWBKXUSZEQ-UHFFFAOYSA-N orixine Natural products C1=C2C(OC)=C(CC(O)C(C)(C)O)C(OC)=NC2=C2OCOC2=C1 UEHVFWBKXUSZEQ-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- 241000223924 Eimeria Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- FWVHWDSCPKXMDB-LSDHHAIUSA-N Febrifugine Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC=CC=C2N=C1 FWVHWDSCPKXMDB-LSDHHAIUSA-N 0.000 description 1
- UIHLDYLKWIWXAH-UHFFFAOYSA-N Febrifugine Natural products OC1CCNCC1CC(=O)CN2C=Nc3ccccc3C2=O UIHLDYLKWIWXAH-UHFFFAOYSA-N 0.000 description 1
- 241001643725 Hydrangea febrifuga Species 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- FWVHWDSCPKXMDB-UHFFFAOYSA-N febrifugine dihydrochloride Natural products OC1CCCNC1CC(=O)CN1C(=O)C2=CC=CC=C2N=C1 FWVHWDSCPKXMDB-UHFFFAOYSA-N 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical class OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- FZGRPBJBMUNMQH-UHFFFAOYSA-N trimethyl-$l^{3}-chlorane Chemical compound CCl(C)C FZGRPBJBMUNMQH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of preparation methods of N n-benzylglycine ethyl esters, include the following steps：Benzylamine is dissolved in organic solvent I, 2 halogenated acetic acids ethyl esters, alkali, quaternary ammonium salt is then added in, N n-benzylglycine ethyl esters is obtained by the reaction.A kind of preparation method of 1 benzyl, 3 piperidone hydrochloride is also disclosed, is concretely comprised the following steps：(1) intermediate compound IV (N n-benzylglycine ethyl esters) is prepared；(2) intermediate compound IV is dissolved in organic solvent II, then adds in 4 halogenated ethyl butyrates, alkali, intermediate III is obtained by the reaction；(3) intermediate III and alkali are reacted, counter regulation pH value is 68, is concentrated under reduced pressure, is extracted with ethyl acetate, washs, dries, is concentrated under reduced pressure to give intermediate II again；(4) intermediate II and acid are reacted, concentrated by rotary evaporation, adds in recrystallisation solvent and crystallize to obtain product.This routine synthetic steps is short, new technology, and intermediate purity is high, and product yield is high, at low cost.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of preparation method of 1- benzyls -3- piperidone hydrochlorides.
Background technology
Halofuginone hydrobromide (Halofuginone, WR237645) also known as bromine chlorine halofuginone hydrobromide, halogen quinoline ketone, Lu's husband's ketone are a kind of from plant
The halogen for the quinazoline ketones alkaloid orixine (Febrifugine) separated in object Changshan (Dichroa febrifuga)
For derivative.Halofuginone hydrobromide has strong insecticidal activity, has stronger inhibitory or killing effect to a variety of Eimeria species, now public by German Hirst
Department's production, trade name " speed is red " ().The chemical structural formula of halofuginone hydrobromide orixine is as follows：
1- benzyl -3- piperidone hydrochlorides are a kind of important chemical intermediates, can be as preparing hydrobromic acid antifebrile dichroanone
Starting material, can be also used for antimicrobial Balofloxacin (Balofloxacin) and Buddhist nun is replaced in anti-leukocythemia stype Shandong
(Ibrutinib) the synthesis such as.The chemical structural formula of 1- benzyl -3- piperidone hydrochlorides is as follows：
Li Weidong et al. discloses a kind of the efficient, succinct of hydrobromic acid antifebrile dichroanone in Chinese patent CN101987843
Preparation method, the starting material of this method is 1- benzyl -3- piperidone hydrochlorides, but does not disclose the starting material in the patent
Preparation method.
The route of synthesis of 1- benzyls -3- piperidone hydrochlorides mainly has following three at present：
(1) Chinese Journal of Pharmaceuticals, 2004,35 (7)：Report is using gamma-butyrolacton as raw material in 385 documents, through benzylamine
Hydrolysis obtains 1- benzyl -3- piperidone hydrochlorides after aminolysis, hydrochloric acid hydrolysis, esterification and bromoacetate condensation, cyclization, reacts
Equation is as follows：
The preparation method route is long, and total recovery is only 18.27%.
(2) Synlett, 2006, (7)：Report is catalyzed using 3- pyridones as raw material by platinum dioxide in 1440 documents
It hydrogenates as 3- hydroxy piperidines, then N is Benzylation, finally aoxidizes hydroxyl and obtains 1- benzyl -3- piperidones, reaction equation for carbonyl
It is as follows：
The hydro-reduction step of the preparation method uses the noble metal catalyst of the high cost such as platinum dioxide, platinum carbon, rises
Beginning raw material 3- pyridones and catalyst cause the cost of this route excessively high.
(3) Chinese patent CN102351783 first passes through N benzyls chemical conversion quaternary ammonium salt, Ran Houyong using 3- pyridones as raw material
Sodium borohydride reduction pyridine ring finally aoxidizes hydroxyl and obtains 1- benzyl -3- piperidones for carbonyl, and reaction equation is as follows：
The hydro-reduction step of the preparation method is transformed to sodium borohydride, finally aoxidizes hydroxyl into ketone using Swern methods,
The cost that the starting material 3- pyridones and sodium borohydride of this route are led is higher, and oxidizing condition is harsh, and temperature is -70 DEG C.
Therefore there is an urgent need for a kind of low cost, easy methods to be used to prepare 1- benzyl -3- piperidone hydrochlorides.
The content of the invention
It is an object of the invention to be directed to more than technical problem, provide a kind of synthetic route shorten, reaction reagent material into
This low, concise production process, preparation method of high-purity 1- benzyl -3- piperidone hydrochlorides.
Technical scheme is as follows：
A kind of preparation method of N- n-benzylglycine ethyl esters, includes the following steps：Benzylamine is dissolved in organic solvent I,
Then 2- halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt are added in, N- n-benzylglycine ethyl esters are obtained by the reaction.
In the above-mentioned technical solutions, the organic solvent I is selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrochysene furan
It mutters, toluene or benzene；The 2- halogenated acetic acids ethyl ester is 2- ethyl chloroacetates or 2- bromoethyl acetates；The alkali is selected from
Triethylamine, diisopropylethylamine, pyridine, sodium carbonate or potassium carbonate；The quaternary ammonium salt is selected from hydrogen sulfate tetrabutylammonium, benzyl chloride
Base triethyl ammonium or dodecyl trimethyl ammonium chloride.
Preferably, the benzylamine, 2- halogenated acetic acids ethyl ester, alkali, the mol ratio of quaternary ammonium salt are 1:1~3:1~3:
0.1~0.5.
A kind of preparation method of 1- benzyls -3- piperidone hydrochlorides, reaction equation are：
It concretely comprises the following steps：
(1) intermediate compound IV (N- n-benzylglycine ethyl esters) is prepared according to preceding method；
(2) intermediate compound IV is dissolved in organic solvent II, the halogenated ethyl butyrates of 4-, alkali is then added in, in being obtained by the reaction
Mesosome III；
(3) intermediate III and alkali are reacted, it is 6-8 to adjust pH value after completion of the reaction, is concentrated under reduced pressure, and concentrate is used
Ethyl acetate extracts, and washing, drying are concentrated under reduced pressure to give intermediate II again；
(4) intermediate II and acid are reacted, revolving obtains concentrate after having reacted, and it is molten that crystallization is added in concentrate
Agent crystallizes to obtain product.
In the above-mentioned technical solutions, in step 2, the organic solvent II is selected from chloroform, carbon tetrachloride, tetrahydrofuran, first
Benzene or benzene；The halogenated ethyl butyrates of 4- are 4- chloros ethyl butyrate or 4- bromobutyrates；The alkali is selected from carbonic acid
Sodium, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide；Preferably, the halogenated butyric acid second of the intermediate compound IV, 4-
Ester, the mol ratio of alkali are 1:1~2:1~3.
In the above-mentioned technical solutions, in step 3, the alkali is selected from sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, first
Sodium alkoxide or potassium methoxide.Preferably, the intermediate III and the mol ratio of alkali are 1:1~3.
In the above-mentioned technical solutions, in step 4, the acid is hydrochloric acid.Preferably, the recrystallisation solvent is selected from second
Nitrile, ethyl acetate or isopropanol；The intermediate II and the mol ratio of acid are 1:3~10.
The beneficial effects of the invention are as follows：The present invention is using benzylamine as starting material and the condensation reaction of 2- halogenated acetic acids ethyl esters, choosing
Generation monoalkylated product N- n-benzylglycine ethyl esters, dialkyl under conditions of organic solvent and alkali are catalyzed down with quaternary ammonium salt
Impurity is effectively controlled, and obtained N- n-benzylglycine ethyl esters purity is high；The present invention also provides prepare the method for the present invention
Obtained N- n-benzylglycine ethyl esters are condensed with 4- halogenated acetic acids ethyl ester, and then cyclization is the piperidine ring of substitution, and finally hydrolysis is de-
Ester, the method that 1- benzyl -3- piperidone hydrochlorides are prepared, this is new synthetic route, this routine synthetic steps is short, technique
Novelty, intermediate purity is high, and low cost of raw materials, technological operation is simple, and product yield is high, quality is good, is easy to industrialize
Production.
Specific embodiment
Embodiment 1 prepares 1- benzyl -3- piperidone hydrochlorides
It operates in accordance with the following steps：
(1) preparation of intermediate compound IV
Benzylamine 43g (0.4mol), acetonitrile 250mL, hydrogen sulfate tetrabutylammonium are sequentially added in the there-necked flask of 1000mL
13.3g (0.04mol), triethylamine 40.4g (0.4mol) are stirred at room temperature, and 2- ethyl chloroacetates 49g (0.4mol) and second is added dropwise
The solution of nitrile 150mL, drop is kept the temperature after finishing reacts 4h at 25-28 DEG C, and HPLC detection reactions are finished, and reaction solution is cooled to quiet at 0-5 DEG C
1.5h is put, is filtered, filtrate decompression is concentrated to give light brown grease (i.e. intermediate compound IV) 80.5g (yield 104%), and HPLC detections are pure
Degree 98.2% is direct plungeed into and reacted in next step.
(2) preparation of intermediate III
Intermediate compound IV 80.5g (0.4mol) prepared by previous step is added in the there-necked flask of 1000mL, adds in tetrahydrofuran
500mL dissolves, and adds in 4- bromobutyrates 78g (0.4mol), adds sodium carbonate 42.4g (0.4mol), and heating stirring is returned
Stream is kept the temperature in 66-68 DEG C of reaction for 24 hours, and after HPLC detection reactions substantially completely, reaction solution is cooled to room temperature, filtering, and filtrate is
Intermediate III is direct plungeed into and reacted in next step, HPLC detection purity 95.2%.
(3) preparation of intermediate II
Intermediate III tetrahydrofuran solution prepared by previous step is added in the there-necked flask of 1000mL, then adds in tertiary fourth
Sodium alkoxide 38.5g (0.4mol) is heated to 66-68 DEG C of anti-lower reflux 5h.After the reaction was complete, reaction solution cooling adds in for HPLC detections
It is 7 that acetic acid 39g, which adjusts pH value, and reaction system is transferred in flask and is concentrated under reduced pressure, and ethyl acetate 500mL is added in concentrate, originally
Water 200mL, stirring layering, is transferred in separatory funnel, and organic layer is washed with water, and then dries, and filtering, filtrate is concentrated to give grease
As intermediate II (N- benzyl -3- oxo-piperidine -4- Ethyl formates) 90.8g, concentrate direct plunges into react in next step, concentration
The HPLC detection purity 92.6% of object.
(4) preparation of target compound I
Intermediate II 90.8g (0.35mol) obtained above is added in the there-necked flask of 1000mL, then adds in concentration
For the concentrated hydrochloric acid 87.5mL (1.05mol HCl) of 12mol/L, 4h is heated to reflux, t=86 DEG C.The reaction was complete for HPLC detections, reaction
System is cooled to room temperature, and reaction solution is rotated (70 DEG C) concentrations removes moisture and hydrogen chloride, and concentrate is separately added into 150mL acetonitriles,
Crystal seed is added in, at room temperature stirring and crystallizing 2-4h, filtering collects off-white color filter cake, is dried in vacuo 4h at 80 DEG C, compound of weighing to obtain
I (1- benzyl -3- piperidone hydrochlorides) monohydrate 63.5g (yield 65.1%), HPLC detects purity 99.4%.
Embodiment 2 prepares 1- benzyl -3- piperidone hydrochlorides
It operates in accordance with the following steps：
(1) preparation of intermediate compound IV
Benzylamine 43g (0.4mol), dichloromethane 250mL, three second of zephiran chloride are sequentially added in the there-necked flask of 1000mL
Base ammonium 45.6g (0.2mol), diisopropylethylamine 154.8g (1.2mol) are stirred at room temperature, and 2- bromoacetates 217.3g is added dropwise
The solution of (1.2mol) and dichloromethane 150mL, drop is kept the temperature after finishing reacts 4h at 25-28 DEG C, and HPLC detection reactions are finished, reaction solution
It is cooled at 0-5 DEG C and stands 1.5h, filter, filtrate decompression is concentrated to give light brown grease (i.e. intermediate compound IV) 75.5g (yields
97.7%), HPLC detects purity 98.4%, direct plunges into and reacts in next step.
(2) preparation of intermediate III
Intermediate compound IV 75.5g (0.39mol) prepared by previous step is added in the there-necked flask of 1000mL, adds in chloroform
500mL dissolves, and adds in 4- chloro ethyl butyrate 152g (0.78mol), adds potassium carbonate 161.5g (1.17mol), heating is stirred
Reflux is mixed, is kept the temperature in 66-68 DEG C of reaction for 24 hours, after HPLC detection reactions substantially completely, reaction solution is cooled to room temperature, filtering, filtrate
As intermediate III, filtrate direct plunges into be reacted in next step, HPLC detection purity 95.7%.
(3) preparation of intermediate II
Intermediate III prepared by previous step is added in the there-necked flask of 1000mL, then adds in potassium tert-butoxide 131g
(1.17mol) is heated to 66-68 DEG C of anti-lower reflux 5h.After the reaction was complete, reaction solution cooling adds in acetic acid 39g tune for HPLC detections
It is 7 to save pH value, and reaction system is transferred in flask and is concentrated under reduced pressure, and ethyl acetate 500mL is added in concentrate, and tap water 200mL is stirred
Layering is mixed, is transferred in separatory funnel, organic layer is washed with water, and then dries, filtering, during filtrate is concentrated to give brown oil as
Mesosome II (N- benzyl -3- oxo-piperidine -4- Ethyl formates) 90.8g, concentrate direct plunges into react in next step, concentrate
HPLC detects purity 93.2%.
(4) preparation of target compound I
Intermediate II 90.8g (0.35mol) made from adding in previous step in the there-necked flask of 1000mL, then adds in dense
The concentrated hydrochloric acid 292mL (3.5mol HCl) for 12mol/L is spent, is heated to reflux 5h, t=86-88 DEG C.The reaction was complete for HPLC detections,
Reaction system is cooled to room temperature, and reaction solution is rotated (70 DEG C) concentrations removes moisture and hydrogen chloride, and it is different that concentrate is separately added into 150mL
Propyl alcohol adds in crystal seed, at room temperature stirring and crystallizing 2-4h, filtering, collects off-white color filter cake, is dried in vacuo 4h at 80 DEG C, weighs
Compound I (1- benzyl -3- piperidone hydrochlorides) monohydrate 58.8g (yield 60.3%), HPLC detects purity 99.6%.
Embodiment 3 prepares 1- benzyl -3- piperidone hydrochlorides
It operates in accordance with the following steps：
(1) preparation of intermediate compound IV
Benzylamine 43g (0.4mol), toluene 250mL, trimethyl chlorine are sequentially added in the there-necked flask of 1000mL
Change ammonium 15g (0.057mol), pyridine 39.5g (0.5mol) stirs at room temperature, be added dropwise 2- ethyl chloroacetates 55g (0.45mol) and
The solution of toluene 150mL, drop is kept the temperature after finishing reacts 4h at 25-28 DEG C, and HPLC detection reactions are finished, and reaction solution is cooled at 0-5 DEG C
1.5h, filtering are stood, filtrate decompression is concentrated to give light brown grease (i.e. intermediate compound IV) 81.0g (yield 105%), HPLC detections
Purity 96.2% is direct plungeed into and reacted in next step.
(2) preparation of intermediate III
Intermediate compound IV 81.0g (0.42mol) prepared by previous step is added in the there-necked flask of 1000mL, adds in toluene
500mL dissolves, and adds in 4- bromobutyrates 117g (0.6mol), adds sodium carbonate 53.0g (0.5mol), and heating stirring is returned
Stream is kept the temperature in 66-68 DEG C of reaction for 24 hours, and after HPLC detection reactions substantially completely, reaction solution is cooled to room temperature, filtering, and filtrate is
Intermediate III, filtrate direct plunges into be reacted in next step, HPLC detection purity 92.8%.
(3) preparation of intermediate II
Intermediate III prepared by previous step is added in the there-necked flask of 1000mL, then adds in sodium tert-butoxide 63.5g
(0.66mol) is heated to 66-68 DEG C of anti-lower reflux 5h.After the reaction was complete, reaction solution cooling adds in acetic acid 39g tune for HPLC detections
It is 7 to save pH value, and reaction system is transferred in flask and is concentrated under reduced pressure, and ethyl acetate 500mL is added in concentrate, and tap water 200mL is stirred
Layering is mixed, is transferred in separatory funnel, organic layer is washed with water, and then dries, and filtering, it is intermediate that filtrate, which is concentrated to give grease,
II (N- benzyl -3- oxo-piperidine -4- Ethyl formates) 92.3g, concentrate direct plunges into react in next step, the HPLC inspections of concentrate
Survey purity 90.9%.
(4) preparation of target compound I
Intermediate II 92.3g (0.35mol) obtained above is added in the there-necked flask of 1000mL, then adds in concentration
For the concentrated hydrochloric acid 230mL of 12mol/L, 6h is heated to reflux, t=86 DEG C -88 DEG C.The reaction was complete for HPLC detections, reaction system cooling
To room temperature, reaction solution is rotated into (68 DEG C) concentrations and removes moisture and hydrogen chloride, concentrate is separately added into 150mL ethyl acetate, adds in
Crystal seed, at room temperature stirring and crystallizing 2-4h, filtering, collects off-white color filter cake, is dried in vacuo 4h at 80 DEG C, target compound of weighing to obtain
I (1- benzyl -3- piperidone hydrochlorides) monohydrate 68.2g (yield 69.9%), HPLC detects purity 99.3%.
Claims (4)
1. a kind of preparation method of 1- benzyls -3- piperidone hydrochlorides, which is characterized in that reaction equation is：
It concretely comprises the following steps：
(1) intermediate compound IV (N- n-benzylglycine ethyl esters) is prepared, is operated in accordance with the following steps：Benzylamine is dissolved in organic solvent I
In, 2- halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt are then added in, N- n-benzylglycine ethyl esters are obtained by the reaction, the benzylamine, 2- are halogenated
Ethyl acetate, alkali, the mol ratio of quaternary ammonium salt are 1:1~3:1~3:0.1~0.5；The organic solvent I is selected from acetonitrile, dichloro
Methane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene or benzene；The 2- halogenated acetic acids ethyl ester for 2- ethyl chloroacetates or
2- bromoethyl acetates；The alkali is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate or potassium carbonate；The quaternary ammonium salt
Selected from hydrogen sulfate tetrabutylammonium, benzyltriethylammonium chloride or dodecyl trimethyl ammonium chloride；
(2) intermediate compound IV is dissolved in organic solvent II, then adds in the halogenated ethyl butyrates of 4-, alkali, intermediate is obtained by the reaction
III；The organic solvent II is selected from chloroform, carbon tetrachloride, tetrahydrofuran, toluene or benzene；The halogenated ethyl butyrates of 4- are
4- chloros ethyl butyrate or 4- bromobutyrates；The alkali be selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or
Person's lithium hydroxide；
(3) intermediate III and alkali are reacted, it is 6-8 to adjust pH value after completion of the reaction, is concentrated under reduced pressure, concentrate acetic acid
Ethyl ester extracts, and washing, drying are concentrated under reduced pressure to give intermediate II again；The alkali be selected from sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide,
Potassium ethoxide, sodium methoxide or potassium methoxide；
(4) intermediate II and hydrochloric acid are reacted, revolving obtains concentrate after having reacted, and recrystallisation solvent is added in concentrate
Crystallization obtains product, and the recrystallisation solvent is selected from acetonitrile, ethyl acetate or isopropanol.
2. the preparation method of 1- benzyls -3- piperidone hydrochlorides as described in claim 1, which is characterized in that in step (2),
The halogenated ethyl butyrate of the intermediate compound IV, 4-, the mol ratio of alkali are 1:1~2:1~3.
3. the preparation method of 1- benzyls -3- piperidone hydrochlorides as described in claim 1, which is characterized in that in step (3),
The intermediate III and the mol ratio of alkali are 1:1~3.
4. the preparation method of 1- benzyls -3- piperidone hydrochlorides as described in claim 1, which is characterized in that in step (4),
The intermediate II and the mol ratio of acid are 1:3~10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511027904.4A CN105622444B (en) | 2015-12-31 | 2015-12-31 | The preparation method of 1- benzyl -3- piperidone hydrochlorides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511027904.4A CN105622444B (en) | 2015-12-31 | 2015-12-31 | The preparation method of 1- benzyl -3- piperidone hydrochlorides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105622444A CN105622444A (en) | 2016-06-01 |
| CN105622444B true CN105622444B (en) | 2018-06-01 |
Family
ID=56037833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201511027904.4A Active CN105622444B (en) | 2015-12-31 | 2015-12-31 | The preparation method of 1- benzyl -3- piperidone hydrochlorides |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105622444B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240561B (en) * | 2018-03-07 | 2020-08-04 | 新发药业有限公司 | Low-cost preparation method of 3-hydroxypyridine |
| CN110878042B (en) * | 2018-09-05 | 2021-06-01 | 新发药业有限公司 | Preparation method of N-substituent piperidine-3-ketone |
| CN110698356A (en) * | 2019-11-07 | 2020-01-17 | 南京恒远科技开发有限公司 | Preparation and purification method of N-benzyl glycine ethyl ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910158B (en) * | 2015-06-15 | 2017-04-12 | 河南师范大学 | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof |
-
2015
- 2015-12-31 CN CN201511027904.4A patent/CN105622444B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN105622444A (en) | 2016-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8884021B2 (en) | Process for preparing racemic nicotine | |
| CN105622444B (en) | The preparation method of 1- benzyl -3- piperidone hydrochlorides | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN101717359B (en) | Method for synthesizing indapamide | |
| CN103936671A (en) | Preparation method for montelukast sodium intermediate | |
| CN114213327A (en) | Synthesis method of (-) -huperzine A | |
| CN113121416A (en) | Preparation method of lefenacin | |
| CN102267994A (en) | Preparation method of moxifloxacin hydrochloride known impurity | |
| CN106554354A (en) | The intermediate of Li Gelieting or its analog and Li Gelieting or the preparation method of its analog | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN101704796B (en) | Preparation method of 3-morpholone | |
| CN102617543A (en) | Synthesis methods for piperonyl ethanol and derivatives thereof | |
| CN103450201B (en) | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine | |
| CN103012260A (en) | Preparation method of pitavastatin calcium intermediate compound | |
| CN103420845A (en) | Method for preparing cinacalcet intermediate R-(+)-1-(1-naphthyl)ethamine | |
| WO2021020998A1 (en) | Method for producing roxadustat | |
| CN106187940A (en) | A kind of one kettle way prepares the method for Febustat | |
| CN103373956B (en) | Method for preparing clevidipine butyrate | |
| CN104892609A (en) | Linagliptin intermediate, preparation method and applications thereof | |
| CN103664940A (en) | Preparation method of moxifloxacin impurity | |
| CN111635358B (en) | Preparation method of hydroxychloroquine | |
| CN115872906A (en) | Levatinib impurity and preparation method thereof | |
| CN110903211B (en) | Preparation method of L-theanine | |
| CN109988162A (en) | One kind is according to piperazine Zole derivatives and preparation method thereof | |
| CN101633639B (en) | High-purity fleroxacin compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |